Drug users constitute a majority of HIV-infected individuals in many poor urban areas in the U.S. Observational studies, including those from our working group, indicate that drug users underutilize antiretroviral therapy, have higher rates of non-adherence, and experience suboptimal treatment outcomes, compared to other HIV-infected demographic groups. Tuberculosis treatment with directly observed therapy (DOT) has proven effective in addressing issues currently being confronted in HIV management. However, translating the tuberculosis DOT model to HIV poses challenges because of salient differences between the two diseases and their management. Methadone maintenance is an effective treatment for opioid dependence and provides a setting in which directly administered antiretroviral therapy (DAART) may be feasible for prolonged periods of time. This approach is conceptually appealing because it facilitates the integration of the traditionally separate realms of HIV medical care and drug dependence treatment. Specific aim 1 is to conduct a randomized, controlled trial of DAART versus self-administered therapy (SAT) in 200 HIV-infected individuals receiving methadone maintenance therapy in one of three clinics in Baltimore, Maryland. Based on encouraging 3-year pilot data, we hypothesize that DAART will be associated with clinically meaningful improvements in HIV treatment outcomes compared to SAT. Our primary study outcome will be suppression of the viral load at 3, 6 and 12 months. Secondary outcomes will include changes in CD4+ cell counts, the development of antiretroviral drug resistance, retention to methadone maintenance therapy, ongoing use of drugs and alcohol, and changes in psychosocial mediators of adherence. We will perform an outcome assessment at 18 months (6 months after DAART has concluded) to assess the durability of the interventional effect. Specific aim 2 is to compare objectively-measured adherence, using electronic medication event monitors (MEMS caps), in the DAART and SAT arms. The development and rigorous assessment of strategies to optimize HIV treatment outcomes in marginalized populations is a high priority. Our research team has an established history of collaboration in this area, and brings together a wealth of research expertise in HIV treatment outcomes, substance abuse, and behavioral aspects of adherence.